Behavior of Protein-Inspired Synthetic Random Heteropolymers

Hilburg, Shayna L.; Ruan, Zhiwei; Xu, Ting; Alexander‐Katz, Alfredo

doi:10.1021/acs.macromol.0c01886

Cited by 33 publications

(51 citation statements)

References 87 publications

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“… 25 − 27 Kratky plots of each PBP revealed bell-shaped curves with a clear local maximum, suggesting that each brush polymer has a compact structure generated by folded chains ( Figure S14c ). 25 , 28 This conclusion was further supported by calculating the Stokes ratio, ρ = R g / R h , for each PBP ( Table S2 ). Generally, for the PBPs, ρ was approximately 0.776, consistent with the expected behavior for spherical particles, including globular proteins.…”

Section: Resultsmentioning

confidence: 64%

Origin of Proteolytic Stability of Peptide-Brush Polymers as Globular Proteomimetics

et al. 2021

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Peptide-brush polymers (PBPs), wherein every side-chain of the polymers is peptidic, represent a new class of proteomimetic with unusually high proteolytic resistance while maintaining bioactivity. Here, we sought to determine the origin of this behavior and to assess its generality via a combined theory and experimental approach. A series of PBPs with various polymer backbone structures were prepared and examined for their proteolytic stability and bioactivity. We discovered that an increase in the hydrophobicity of the polymer backbones is predictive of an elevation in proteolytic stability of the side-chain peptides. Computer simulations, together with small-angle X-ray scattering (SAXS) analysis, revealed globular morphologies for these polymers, in which pendant peptides condense around hydrophobic synthetic polymer backbones driven by the hydrophobic effect. As the hydrophobicity of the polymer backbones increases, the extent of solvent exposure of peptide cleavage sites decreases, reducing their accessibility to proteolytic enzymes. This study provides insight into the important factors driving PBP aqueous-phase structures to behave as globular, synthetic polymer-based proteomimetics.

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Section: Resultsmentioning

confidence: 64%

Origin of Proteolytic Stability of Peptide-Brush Polymers as Globular Proteomimetics

et al. 2021

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“…Herein, we explore RHP behavior using unbiased atomistic molecular dynamic methods with the Amber MD package, similar to our prior work. 10,26 Through a series of successive anneal cycles to 500 K in implicit water, ten conformations each of two distinct polymer sequences were created and then annealed to 650 K in explicit solvent: water, DMSO, THF, or hexane. The resulting single chain conformations at 300 K from these simulations were used for analysis.…”

Section: Lettermentioning

confidence: 99%

“…The two random heteropolymer sequences investigated, Sequence 1 and Sequence 2 as shown in Figure 1, are composed of the methacrylate-based building blocks studied previously. 10 Sequence 1 contains all four monomer species-methyl methacrylate (MMA), oligo(ethylene glycol)methacrylate (OEGMA), 2-ethylhexyl methacrylate (EHMA), and 3-sulfopropyl methacrylate (SPMA)-used in the prior work, while Sequence 2 is similar but lacks the anionic SPMA monomer. Both sequences formed compact globular structures in water and hexane, with distinct surface compositions in each solvent apparent by visual inspection in Figure 1.…”

Section: Lettermentioning

confidence: 99%

“…8,9 We previously studied a specific RHP design-space through molecular dynamics (MD) simulations and elucidated the resulting SCNP structure and dynamics. 10 The work demonstrated that while theories are helpful in understanding these polymer systems, the inclusion of specific chemistries is necessary for a full picture of the molecular behavior. While the work has been pivotal in gaining a mechanistic picture of how the RHPs behave in water, several potential applications occur in, or require processing steps performed in, other solvents.…”

Section: Lettermentioning

confidence: 99%

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Solvent Remodeling in Single-Chain Amphiphilic Heteropolymer Systems

Hilburg

Alexander‐Katz

2021

Preprint

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Through molecular dynamics simulations, we demonstrate how single-chain nanoparticles (SCNPs) assembled via transient linkages in water can remodel in organic solvent. Methacrylate-based random heteropolymers (RHPs) have shown promise in an assortment of applications that harness their bio-inspired properties. While their molecular behavior has been broadly characterized in water, many newer applications include the use of organic solvent rather than bio-mimetic conditions in which the polymer assemblies, typically driven by the hydrophobic effect, are less well understood. Here, we examine a specific RHP system which forms compact globular morphologies in highly polar and non-polar environments while adopting extended conformations in solvents of intermediate polarity. We also demonstrate the pivotal role of electrostatic interactions between charge groups in low dielectric mediums. Finally, we compare high temperature anneal cycles to room temperature equilibrations to illuminate activation barriers to remodeling upon environmental changes.

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“…Recent studies have shown that synthetic random heteropolymers with statistically controlled side chain compositions are able to exhibit protein-like functions even without the peptide backbone. [6][7][8][9] To this end, synthetic polypeptides prepared by the ring-opening polymerization (ROP) of N-carboxyanhydrides (NCA) have emerged as promising protein mimics with the potential to synergize the advantages of both peptides and synthetic polymers. [10][11][12][13][14][15] Specifically, polypeptides possess the same backbone and secondary conformations as protein and can be efficiently produced at up to kilogram scales and a high number-averaged molecular weight (Mn).…”

Section: Introductionmentioning

confidence: 99%

A High-Throughput Platform for Efficient Exploration of Functional polypeptides Chemical Space

Zhou

Zhang³

et al. 2022

Preprint

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Rapid and in-depth exploration of the chemical space of high molecular weight synthetic polypeptides via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is a viable approach towards protein mimics and functional biomaterials. The traditional synthetic workflow, however, has been labour-intensive and with limited throughput. Here, we develop an efficient chemistry for the high throughput diversification of polypeptides based on a click-like reaction between selenolate and various electrophiles in aqueous solutions. Importantly, the platform is amenable to automation, which allows rapid generation of up to 1200 homopolypeptides or random heteropolypeptides (RHP) within one day. With the assistance of machine learning, iterative exploration of the RHP library efficiently and effectively identifies candidates with improved glutathione peroxidase-like activity from complex chemical space of which we have little prior knowledge. This automated and high-throughput platform provides potential solutions to unmet challenges such as de novo design of artificial enzyme, biomacromolecule delivery, and understanding of intrinsically disordered proteins.

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Behavior of Protein-Inspired Synthetic Random Heteropolymers

Cited by 33 publications

References 87 publications

Origin of Proteolytic Stability of Peptide-Brush Polymers as Globular Proteomimetics

Origin of Proteolytic Stability of Peptide-Brush Polymers as Globular Proteomimetics

Solvent Remodeling in Single-Chain Amphiphilic Heteropolymer Systems

A High-Throughput Platform for Efficient Exploration of Functional polypeptides Chemical Space

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